Acute pain after orthopedic surgery should be anticipated and its treatment should be a part of every anesthetic plan. Analgesic approaches have changed in recent years in part due to patient expectations, the shift toward ambulatory surgery, and shorter hospital stays. Further, analgesic options have increased with new drugs and modes of delivery. Some of the improvement in management of acute pain is based on a greater understanding of the neural pathways and mechanisms involved in the stages of acute pain. There is also increasing interest in the strategy of preventing pain before it is perceived — “pre-emptive analgesia.” Non-steroidal anti-inflammatory drugs, local anesthetics, adrenergic agents, and novel methods of applying opioids have been added to conventional parenteral analgesics, and thus increasing the options for acute pain control. Using more than one analgesic option (multi-modal analgesia) — ideally with different mechanisms — may achieve improved pain control with decreased side-effects.
Management of acute pain after orthopedic surgery has changed significantly during the last decade. Formerly a task relegated to residents and ward nurses, analgesia is now being managed by increasingly large numbers of Anesthesiologists and members of surgical teams. This change is driven, in part, by increasing expectations from patients who hear from the lay press that excellent control of pain is possible and should be considered in selecting physicians and health care facilities.¹ Also there is increasing evidence that acute pain may cause postoperative complications and that excellent analgesia may improve outcome after surgery as measured by a variety of factors.² Acute pain results in hemodynamic changes, such as hypertension, tachycardia, and increased tissue oxygen demand, which can cause myocardial ischemia. Acute pain can decrease ventilation, prevent effective pulmonary toilet, and predispose the patient to pulmonary complications. Severe acute pain causes metabolic and hormonal changes that inhibit fibrinolysis. This inhibition of fibrinolysis may increase thrombotic complications, such as deep venous thrombosis and pulmonary embolism, which are the leading causes of morbidity after elective reconstructive orthopedic surgery.
The development of devices such as patient controlled analgesia (PCA) pumps have increased options for effectively treating acute pain. The traditional, on-demand parenteral opiate strategy accomplishes analgesia but has some limitations. Severe pain motivates the patient to request analgesia. The lag period that follows between demand and delivery allows the pain to become excruciating. Experienced surgeons recognize that pain is often extreme by the time that treatment is finally administered, so they order larger doses that have a potent analgesic effect. However, as the dose increases, so does the potential for sedation and respiratory depression. These limitations have led to the development of (PCA) for opioid delivery. The risk of respiratory depression with large doses of on-demand opioids has increased use of non-opioid analgesics and regional anesthesia for acute pain control in orthopedic patients. Combinations of these options are also being prescribed, to achieve the optimal analgesia with the lowest side-effect profile. The level of pain control and the incidence of sedation that occurs with traditional, on-demand opiate treatment has been compared to PCA approaches, and the PCA patients have superior analgesia with less variability and less total opioid than demand patients.³ The further observation that patients medicated with parenteral opiates before surgery exhibited less acute postoperative pain led to the question of whether analgesics — given before the establishment of acute pain — decreased postoperative pain. This approach has been called “pre-emptive” and considerable work has been performed to determine the clinical relevance of various pre-emptive analgesia strategies.
It is the purpose of this review to discuss the mechanisms of acute, postoperative pain in orthopedic patients, to discuss strategies for treatment, and explore the potential role for a strategy of pre-emptive analgesia.
Mechanisms of Acute Pain
Acute pain after orthopedic surgery is the result of tissue injury from the procedure. The link between a surgical incision and the pain experienced by the patient is mediated by distinct neural pathways. The surgical intervention activates receptors (nociceptors), which send a signal from the site of surgery via slow conducting A delta and C fibers within peripheral nerves, which are geographically integrated in the dorsal column of the spinal cord, and transmitted rostrally to the brain. The signal is transmitted up the spinal cord in the lateral spinothalamic tracts into the lateral thalamus and is projected geographically onto the sensory cortex. Further modulation is possible at any of the upward transmission sites. An understanding of the anatomy and biochemistry involved in such transmission is essential to the treatment and prevention of acute pain.
Peripheral Receptors and Nerve Transmission
The receptors activated by tissue injury (nociceptors) are the specialized terminal ends of small nerve fibers in the tissue. Although a few nociceptors are highly specialized and respond only to very limited types of stimuli, most are activated by almost any chemical, thermal or mechanical disruption. The A delta and C fibers conduct 5 to 10 times slower compared to those that control motor activity and fine sensory discrimination. However, A delta and C fibers are the most common peripheral nerve fibers, and stimulation causes a nociceptive signal to be conducted centrally.
Tissue injury also causes nociceptors to release a number of chemical mediators, such as bradykinin, serotonin, substance P, and histamine. Substance P increases the sensitivity of peripheral receptors such that the threshold for signal conduction decreases (allodynia); consequently, receptors are more frequently activated. This increased activity is termed hypersensitivity.⁴ In addition, most of these mediators are potent vasodilators and degranulate mast cells, releasing histamine, which is also a potent vasodilator. This sensitization of peripheral nociceptors is further increased by chemical messengers of tissue injury, which leak from damaged cells, such as potassium, serotonin, histamine, bradykinin, leukotrienes and prostaglandin. The combination of edema, vasodilation and the direct effects of tissue-injury mediators maximally stimulates mechanical receptors. The gradually increasing transmission from peripheral nociceptors, and the accompanying perception of increased pain from decreasing levels of stimulation is termed hyperalgesia.
When an inflammatory state is induced experimentally, previously silent A delta and C fibers become actively nociceptive when the joint is moved through its normal range of motion.
Study of experimental arthritis in the cat knee joint has revealed that nerve endings are recruited to take on a nociceptive function in response to tissue injury and inflammation.⁵ The majority of peripheral nerve receptors are multi-functional and under normal conditions are not nociceptive. When an inflammatory state is induced experimentally, previously silent A delta and C fibers become actively nociceptive when the joint is moved through its normal range of motion. The clinical equivalent is the acute pain occurring during joint motion after intraarticular surgery. These “silent” receptors are responsible for the secondary phase of acute pain after joint surgery. At wound sites not within joints, peripheral hypersensitivity results in similar recruitment of previously “silent” receptors in the tissues surrounding the wound site.⁶ Minimal stimulation causes these receptors to transmit nociceptive signals, and trivial contact with the patient causes severe pain that is greatly out of proportion to the apparent stimulus, and is described as hyperalgesia.
Spinal Cord Integration of Nociceptive Signals
Signals are transmitted via small fibers within the substance of peripheral nerves toward the spinal cord. As the A delta and C fibers approach the spinal cord, they move ventrolateral to synapse geographically in the gray matter of the dorsal horn. Numerous neurotransmitters are involved in primary and interneuron synapses, including gamma aminobutyric acid, glutamic acid, substance P, somatostatin, vasoactive intestinal peptide, and cholecystokinin octapeptide.⁷ These neurotransmitters allow transmission rostral from the dorsal columns, through the spinothalamic tracts cephalad toward the thalamus.
Spinal Cord Modulation
A variety of other factors can modify the nociceptive signals once they have entered the spinal column. The collateral fibers of the large A alpha and beta fibers, responsible for motor activity and fine sensation, synapse in the dorsal columns. These connections can decrease nociceptive transmission. The clinical equivalent is the urge to move the injured area after acute injury. The converse may also occur, with involuntary muscle activity increasing pain.
In addition to local synapses, there are descending tracts originating in the brain stem that modulate nociceptive transmission. Activation of these descending tracts decreases cephalad transmission of nociception at the spinal cord level. Much of the analgesic effect of systemic opiates occurs by activation of these descending control paths.⁸
Spinal cord reflexes can be activated by peripheral nociceptive transmission. Tissue damage activates an afferent reflex cycle, which causes involuntary movement or muscle spasm.⁹ Autonomic reflexes cause vasospasm of the microcirculation in the injured area. This vasospasm increases skeletal muscle spasm which increases nociceptive transmission from the site. Nociceptive transmission is also modulated by the rate of transmission. Sustained stimulation from an injury or surgical incision starts with a limited number of nociceptive signals, which reach the dorsal column. When the peripheral site becomes hypersensitive, transmission greatly increases, especially as surrounding silent and non-nociceptive receptors are recruited for nociceptive transmission. Over time, as the number of signals increases, there is accumulation of neurotransmitters, which are mostly aminoacids and that cause a sustained change in the biochemistry around the dorsal horn cells. The receptor threshold decreases, and the signal strength required for cephalad nociceptive transmission decreases.¹⁰ The receptor field also expands to include tissues that were previously not involved in the injury transmission. This phenomenon is referred to as receptor plasticity and is mediated by sustained, self-propagating depolarization.¹¹ The net effect of these changes is central hypersensitivity and is also referred to as “wind-up.”¹² Wind-up is thought to be the cellular mechanism for the hyperacute phase of postoperative pain, when the amount of pain seems to greatly exceed the stimulus and causes muscle spasm. Tissue surrounding the wound is sensitive and pain is perceived during movement even at considerable distance from the site of surgery.
Pain Perception in the Brain
The signals from the dorsal horn synapse with receptor cells and inter-neuron linkages enter the lateral spinothalamic tract at the same spinal level as they entered and few segments rostral and caudal. They ascend into the thalamus, where some synapse directly with the somatosensory cortex to produce acute sensation and some synapse in the brainstem reticular formation, where they participate in the downward pathways that modify nociceptive transmission. These synapses also project to the frontal cortex in non-somatosensory areas and are responsible for some of the emotional aspects of pain perception.
A unique aspect of orthopedic surgery is that large amounts of tissue injury messengers are released. Exposure of fractures, osteotomy, or the reaming of long bones liberates copious amounts of histamine, bradykinin, serotonin, prostaglandins, and substance P.
The Physiology of Pain in Orthopedic Patients
The origin of pain in orthopedic patients begins with an injury or a painful, degenerative process that requires reconstruction or palliation. The surgical incision creates an additional nociceptive stimulus, as does manipulation of soft tissues and bone, whose periosteum is richly innervated with mechanical nociceptors. A unique aspect of orthopedic surgery is that large amounts of tissue injury messengers are released. Exposure of fractures, osteotomy, or the reaming of long bones liberates copious amounts of histamine, bradykinin, serotonin, prosta-glandins, and substance P.
Another unique aspect of orthopedic surgery, implicated in the creation of acute pain, is the high probability that many surgical procedures will cross several dermatomes. Each dermatome will have nociceptors which signal the dorsal column of the spinal cord at that spinal level. The active, repetitive nociception at several adjacent dermatomes magnifies the stimulus so as to expand the pain receptor fields in the spinal column and increase the potential for central hypersensitivity.
On the positive side, much of orthopedic surgery is ideally suited to the use of regional anesthesia, and for reasons discussed below, the use of local anesthetics at various sites may be the most effective approach to both the treatment and prevention of acute pain. Proposed mechanisms for pre-emptive analgesia¹²˒¹³ can form the basis for discussion of future directions in pain relief.
Therapeutic Options for Pain Relief
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs). The mechanism of analgesia which occurs from NSAIDs results from their ability to interfere with the peripheral production of tissue injury pain mediators.¹⁴ A decrease in production of eicosanoid precursors of prostaglandins from arachidonic acid decreases the amount of these mediators, which are mainly prostaglandin derivatives. This should decrease peripheral sensitization and nociceptor transmission. Also, some evidence shows that parenteral NSAIDs act on the central nervous system. The selective blockade of the excessive secretion of dorsal horn excitatory transmitters such as excitatory amino acids and nitric oxide, may be selectively preventing central hypersensitization. Experimental evidence shows that parenteral NSAIDs and central opioids act synergistically, and current investigation of spinally administered NSAID drugs¹⁵ is directed at this possible action. The potential for NSAIDs to prevent recruitment of silent nociceptors could have a role in pain relief for soft tissue and intraarticular wounds. Studies of patients treated with NSAIDs have demonstrated beneficial effects of reduced edema and hypermetabolism at the surgical site¹⁶ as well as decreasing the stress response postoperatively.¹⁷ The side effect profile can limit the analgesic use of NSAIDs. NSAIDs cause a small decrease in renal blood flow, which should be clinically silent except in those patients with limited renal reserves or who are hypovolemic. There is some potential for parenteral ketorlac resulting in acute renal failure, although this is usually reversible without the need for dialysis. Irritation of gastrointestinal mucosa and interference with coagulation are the other issues.
Regional Anesthesia. Conduction block at the surgical site or anywhere on the pathway to the spinal cord acts provides effective analgesia.¹⁸ Peripheral nerve block, field block and wound infiltration are the choices routinely available for orthopedic patients. Brachial or lumbosacral plexus blockade with a catheter can accomplish this objective for a large percentage of extremity procedures. For those cases in which catheter placement is not applicable or technically possible, single-shot peripheral nerve or plexus block with long-acting local anesthetics, such as bupivacaine, ropivacaine or mepivacaine compounded with tetracaine, is a good alternative. Recent work has suggested that injection of local anesthetic into joint spaces¹⁹ decreases postoperative pain after intraarticular surgery. The analgesia achieved greatly outlasts the duration of action of the local anesthetic agent injected, especially if combined with morphine.²⁰ When epinephrine is used for vasoconstriction, the adrenergic agent increases the analgesic quality of the intraarticular injections.²¹ The existence of peripheral opiate receptors has been established. In addition, local anesthetics and opioids may interfere with the acute inflammatory response. Receptor activity is mediated by potassium and calcium. Local anesthetics influence ionic channel activity, and opiate effects are modulated by calcium and calcium channel antagonists.
Some clinical work suggests that opiates given as pre-medication prolong the interval from the end of surgery to the first postoperative request for pain relief suggesting a possible pre-emptive effect.
Parenteral Narcotics. Classic pain control with on-demand parenteral opiates remains the most common analgesic choice in the United States. Some clinical work suggests that opiates given as pre-medication prolong the interval from the end of surgery to the first postoperative request for pain relief suggesting a possible pre-emptive effect. Pre-medication with opiates of orthopedic patients is probably common because many patients have injuries for surgical repair or painful arthritic conditions that require joint reconstruction, so the pre-operative analgesic effects may have a pre-emptive effect during and after surgery. Using PCA opiates, improved analgesia has been achieved based on a level administration of the agent, a steady amount of pain, and avoidance of hyper-acute pain, which requires very large doses to achieve analgesia.³ Morphine is the best known agent and readily lends itself to both parenteral, on-demand, and PCA delivery. The side effects of opioids are dose-dependent respiratory depression, followed by nausea and a smaller incidence of pruritis and urinary retention. Meperidine is a comparable agent, with PCA use being limited by the accumulation of a metabolic product, normeperidine. Accumulation of normeperidine results in CNS excitation, initially manifested by agitation and tremor and which can progress to seizure activity. The synthetic opioids, such as fentanyl and sufentanyl, are more potent with a more rapid onset and shorter half life. The advantage of these drugs is a rapid onset with fewer side effects such as itching and urinary retention, although the short duration makes the continuous administration by pump or a PCA device mandatory. Opiate agonist-antagonist agents, such as nalbuphene, have been used in orthopedic patients, although the ceiling of analgesia with these agents is often too low to achieve good pain control after surgery and further analgesia with opiate agonists is then complicated by the partial antagonist properties.
Central Application of Analgesics. Orthopedic surgery in many cases involves the spine or lower body, so the central application of local anesthetics, opioids and other agents is an effective strategy for analgesia. Although somatosensory evoked potentials indicate intact A delta and C fiber conduction to the dorsal columns during spinal and epidural anesthesia, effective analgesia remains during the duration of the blocks. With spinal anesthesia alone, the pre-emptive effect may be limited because conduction occurs during the block and resolution of the block allows hypersensitization to occur. When epidural anesthesia is extended into the postoperative period as analgesia, the pre-emptive analgesic effect should be excellent, although not as complete as peripheral conduction block which totally interrupts nociceptive transmission. Use of adjuncts to central local anesthetics can improve their pre-emptive effect. These include opiates and adrenergic agonists such as clonidine and possibly epinephrine. Synergistic mechanisms at the spinal cord level²²˒²³ may make the local anesthetic, opiate combination ideal. Pre-clinical work with other agents that theoretically interfere with hypersensitivity, wind-up and cephalad transmission of nociception has begun with keterolac,¹⁴ ketamine,²⁴ calcium,²⁵ calcium channel antagonists,²⁶ GABA inhibitors, serotonin antagonists, and others. Using agents in the subarachnoid space is limited by the need to verify that these agents are not neurotoxic.
Clinical Studies of Acute Pain in Orthopaedic Patients
Preemptive Analgesia. One of the early observations that led to a renewed interest in the concept of preventing postoperative pain was the report of McQuay.²⁷ In this study, if the patients received an opiate pre-medication prior to orthopaedic surgery, their interval to first request for pain medicine was significantly prolonged and the total opiate required in the first 24 hours was reduced. This preventative effect was also found after elective lumbar spine surgery, reported by Kiss.²⁸ Almost 50% of the patient who received an opiate pre-medication required no parenteral opiates within the first 24 hours after surgery. A preemptive effect was also reported by Taivainen²⁹ in trauma surgery patients who were given parenteral indomethacin starting in the emergency room, although there was some additional postoperative bleeding noted in a qualitative manner.
Shoulder Surgery. Regional anesthesia is the most common approach to complete analgesia after shoulder surgery. Haasio³⁰ reported minimal need for supplemental opiates after shoulder surgery with an interscalene catheter, although 10% of the patients experienced at least mild signs of local anesthetic toxicity within the 24 average hours that the catheter was used. Single-shot interscalene placement of meperidine was reported by Davidas,³¹ with long duration analgesia (up to 24 hours) after open shoulder procedures. Brandl³² advocates interscalene block with bupivacaine as a part of a balanced anesthetic technique for both intraoperative anesthesia and extended postoperative analgesia for up to 24 hours after open shoulder procedures. The use of continuous interscalene block resulted in severe bupivacaine toxicity in a case reported by Tuominen³³ involving the migration of the catheter into an artery at a prolonged interval after the placement.
Hip Fracture. Much of the information about pain control after hip fracture centers around the advantages of regional anesthesia. Although intrathecal opiates have been tried, the high incidence of delayed respiratory depression in the advanced geriatric patient has decreased the enthusiasm for this technique. Continuous epidural catheter use has established efficacy. Hood³⁴ reported significant reduction of pain within the first 24 hours after hip fracture repair under general anesthesia when a femoral nerve block was compared to intraoperative parenteral opiates. Coad³⁵ found even greater opiate sparring when the femoral block was performed prior to incision.
Spine Surgery. Pain control after elective spine surgery has been extensively studied, with application of local anesthetics and opiates into the epidural space and the subarachnoid space, as well as parenteral use of NSAIDs. Wound injection with 0.5% bupivacaine was reported by Milligan³⁶ who found increased time interval to first request of pain medication and decreased total morphine for the first 24 hours. Otto³⁷ found that 0.25% bupivacaine in the epidural space eliminated pain during the first 24 hours after surgery.
Epidural and subarachnoid opioids after spine surgery has also been extensively studied. Joshi³⁸ compared intravenous fentanyl to epidural fentanyl and found improved pain scores and decreased morphine use in the epidural fentanyl group. Bourke³⁹ compared epidural to intramuscular morphine and demonstrated significantly improved analgesia with the epidural application. Waikakul⁴⁰ compared directly-applied epidural morphine to saline and found 15 hours of complete pain relief in the study group. Intrathecal morphine also provided profound, long-lasting analgesia in the report of Ross⁴¹ without any respiratory depression that required treatment, although a significant number had at least one interval where respiratory rate decreased below 12 during the 6 to 18 hour interval after injection.
In another study of total knee patients, continuous three-in-one block provided excellent analgesia in the postoperative period, which resulted in improved range of motion of the knee at discharge.⁵⁰
NSAIDs have been used for analgesia after spine surgery. Rectal⁴² and intravenous⁴³ indomethacin provided partial pain control after lumbar disc surgery. Preoperative intravenous naproxen⁴⁴ increased the interval to first analgesic request after lumbar laminectomy and decreased the total morphine for up to 24 hours.
Total Joint Replacement. Pain control after total hip and total knee replacement has been reported with central blocks, peripheral nerve blocks and a variety of parenteral supplements to conventional opiate treatment. The standard of comparison is intravenous morphine, administered with a patient-controlled analgesia device. Although analgesia can be achieved, excessive sedation can occur. Epidural morphine provided superior pain control compared to intravenous morphine in the report of Weller,⁴⁵ but there were more side effects, including pruritis and decreased ventilation. Modig⁴⁶ compared epidural morphine to epidural bupivacaine, finding improved pain control in the morphine group, but serious side effects, including respiratory depression that required treatment. Intrathecal morphine in low doses has been reported to provide excellent analgesia with a long duration and no side effects.⁴⁷ Drakeford⁴⁸ found equivalent analgesia with dilaudid and morphine with both providing complete pain control for as much as 24 hours.
Lumbar plexus block with the three-in-one approach or continuous technique have been used for pain control after total knee and total hip replacement. Serpell⁴⁹ placed a catheter in the femoral nerve sheath in total knee replacement patients and achieve a significant — though not complete — analgesia with an infusion of 0.5% bupivacaine, with an ipsilateral motor block. In another study of total knee patients, continuous three-in-one block provided excellent analgesia in the postoperative period, which resulted in improved range of motion of the knee at discharge.⁵⁰ Three-in-one block has also been reported as an approach to pain control after total hip replacement⁵¹ with incomplete analgesia and significant motor block.
NSAIDs have been used as a part of pain control after total joint replacement. When used after surgery, they complement opiate analgesia.⁵² When given prior to the conclusion of surgery, improved analgesia is achieved with opiates.⁵³ Because of the risk of bleeding, NSAIDs are to be avoided when low molecular weight heparin is planned for prophylaxis of deep venous thrombosis. Clonidine⁵⁴ and metoclopramide⁵⁵ have demonstrated additive analgesia with opiates, presumably by interfering with the peripheral or central mechanisms of hypersensitivity.
Knee Surgery. The one area where pain control after orthopaedic surgery has been studied the most has been knee surgery. Epidural analgesia, nerve blocks and parenteral agents are the conventional approaches. In addition, there is increasing evidence that direct application of agents into the intraarticular space provides a unique combination of analgesia without side-effects.
Epidural analgesia provides excellent pain control and pain free range of motion after open ACL repair.⁵⁶ Femoral nerve block performed prior to surgery reduced the need for opiate by 80% compared to control with a single injection of 0.5% bupivacaine.⁵⁷ NSAIDs had a similar profile of pain control after knee surgery as total joint replacement, being more effective when given prior to surgery as opposed to postoperatively.⁵⁸
The observation that patients who received arthroscopic surgery under local anesthesia seem to have less postoperative pain than patients with comparable arthroscopic procedures performed under general anesthesia lead to investigations to explain this phenomenon. The idea that intraarticular analgesia that persists into the postoperative period could be achieved by injection of local anesthetics and/or opiates into the joint prior to surgery was considered a possible explanation. A clinical study of intraarticular pain control was reported by Stein.⁵⁹ A very small (1-mg) dose of morphine provided complete pain relief for up to 18 hours after intraarticular arthroscopic surgery of the knee. This pain control was not achieved by the same dose injected intravenously either in quality or duration and was eliminated when naloxone was injected into the intraarticular space. Khouri⁶⁰ evaluated morphine, bupivacaine, and a combination of the two after surgical arthroscopy and found the combination to be superior to either element alone when injected at the conclusion of surgery. Pain control after anterior cruciate ligament reconstruction has also been evaluated. With non-arthroscopic ACL repair, intraarticular morphine was significantly better than saline administered at the conclusion of surgery, injected by needle away from the wound after the joint was sealed and the drain clamped.⁶¹ Intraarticular bupivacaine and morphine provided excellent analgesia when injected prior to incision for arthroscopically-assisted ACL repair.⁶²
Multi-Modal Analgesia. Because the pain mechanism has a number of steps and the pain state itself is dynamic, using multiple approaches to prevent and treat acute pain may be advantageous. Much like “balanced anesthesia” in the operating room, combinations of agents — perhaps with different mechanisms of action — could create “multi-modal” analgesia.⁶³ An attractive possibility is that the doses of the individual agents could be reduced while maintaining the same level of analgesia, thereby decreasing the incidence of side effects from each.²²˒²³ Clinical evidence shows that combinations of local anesthetics and synthetic opiates at low concentrations provide excellent analgesia for orthopedic patients in the postoperative period with minimal side effects. Whether these interventions, established before surgery and maintained into the postoperative period, provide relief superior to the same approach started after surgery remains to be definitively established.
The overall link between acute pain and the amplification of the pain has led to the concept of pain prevention, namely “pre-emptive analgesia,” with analgesic choices applied before surgery to prevent or significantly decrease acute pain.
Conclusion
Acute pain is a common occurrence after orthopedic surgery. Approaches to control such pain have changed in response to an improved understanding of the neuroanatomy of acute pain and from patient requests for better analgesia. The clinical behavior of peripheral receptors is now better understood — as is their role in the postoperative cycle of pain in which pain leads to increasing tissue sensitivity, muscle spasms, edema and perpetuation of the pain. These peripheral changes can be prevented with physical and pharmacologic interventions. The role of the spinal cord and the plasticity of dorsal column receptors in acute pain has been established, with acute pain causing increased sensitivity and increased rates of nociceptive transmission. Prevention of these changes has established advantages in pain control. The overall link between acute pain and the amplification of the pain has led to the concept of pain prevention, namely “pre-emptive analgesia”, with analgesic choices applied before surgery to prevent or significantly decrease acute pain. With agents available that can act at many sites — such as the receptors, peripheral nerves, the spinal cord, and in the brainstem — synergism can be achieved. Multi-modal pre-emptive analgesia is the basis for the increasingly common use of multiple agents to achieve pain control. Using agents that can be delivered continuously, especially those that can be controlled by the patients themselves, has increased patient satisfaction and improved the quality of analgesia achieved.
Future directions involve identifying specific antagonists to the substances released by tissue injury and identifying antagonists to nociceptive neurotransmitters or alternatively, selective agonists of inhibitory nociceptive pathways. Treatment strategies may involve substances placed within the wound site, in the pathway of peripheral transmission, or at sites within the CNS. The goal should be a “pain-free” postoperative period.